1. A non-randomized trial to assess the safety, tolerability, and pharmacokinetics of posaconazole oral suspension in immunocompromised children with neutropenia
- Author
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Amita Joshi, Thomas J. Walsh, Eric Mangin, Andreas H. Groll, Lillian Sung, Patricia Carmelitano, C. Michel Zwaan, Hetty Waskin, Nicholas A. Kartsonis, Davis Gates, John S. Bradley, Amanda Paschke, Antonio Arrieta, Thomas Lehrnbecher, Ngo, Doan TM, Ngo, Doan T. M., and Pediatrics
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0301 basic medicine ,Male ,Posaconazole ,Antifungal Agents ,Administration, Oral ,Pediatrics ,law.invention ,White Blood Cells ,0302 clinical medicine ,Randomized controlled trial ,Animal Cells ,law ,Neoplasms ,Medicine and Health Sciences ,030212 general & internal medicine ,Prospective Studies ,Prospective cohort study ,Child ,Pediatric ,Multidisciplinary ,Pharmaceutics ,Age Factors ,Adjustment of Dosage at Steady State ,Infectious Diseases ,Tolerability ,Research Design ,Child, Preschool ,Area Under Curve ,6.1 Pharmaceuticals ,Administration ,Medicine ,Female ,Cellular Types ,Drug ,Pediatric Infections ,Research Article ,medicine.drug ,Oral ,medicine.medical_specialty ,Neutropenia ,Adolescent ,Clinical Research Design ,General Science & Technology ,Immune Cells ,Science ,Immunology ,030106 microbiology ,Clinical Trials and Supportive Activities ,Antineoplastic Agents ,Research and Analysis Methods ,Drug Administration Schedule ,Beverages ,Dose-Response Relationship ,03 medical and health sciences ,Immunocompromised Host ,Dose Prediction Methods ,Drug Therapy ,Pharmacokinetics ,Clinical Research ,Internal medicine ,medicine ,Humans ,ddc:610 ,Adverse effect ,Preschool ,Nutrition ,Blood Cells ,Tea ,Dose-Response Relationship, Drug ,business.industry ,Biology and Life Sciences ,Infant ,Evaluation of treatments and therapeutic interventions ,Cell Biology ,Triazoles ,medicine.disease ,Diet ,Clinical trial ,Age Groups ,People and Places ,Population Groupings ,Adverse Events ,business ,Invasive Fungal Infections - Abstract
Author(s): Arrieta, Antonio C; Sung, Lillian; Bradley, John S; Zwaan, C Michel; Gates, Davis; Waskin, Hetty; Carmelitano, Patricia; Groll, Andreas H; Lehrnbecher, Thomas; Mangin, Eric; Joshi, Amita; Kartsonis, Nicholas A; Walsh, Thomas J; Paschke, Amanda | Abstract: BACKGROUND:Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS:This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to l18 years; AG2, 2 to l7 years; and AG3, 3 months to l2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS:The percentage of subjects meeting the PK target was l90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to l7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to l18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to l18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION:The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01716234.
- Published
- 2019